PAPER: The gene that can transform mild influenza in to a life threatening
disease

30 March 2012

A
genetic finding could help to explain why influenza becomes a life-threatening
disease for some people, and yet has only a mild effect on others. Collaborative
research led by scientists at UCL and the Wellcome Trust Sanger Institute found
that people who carry a particular variant of the IFITM3 gene are significantly
more likely to be hospitalised when they fall ill with influenza than those who
carry other variants.

The
gene plays a critical role in protecting the body against infection with
influenza and a rare version of it appears to make people more susceptible to
severe forms of the disease. The results are published in the journal Nature.

IFITM3
is an important protein that protects cells against virus infection and is
thought to be crucial in the immune system's response against such viruses as
H1N1 pandemic influenza, commonly known as ‘swine flu’. When the protein is present in large
quantities, the spread of the virus in lungs is hindered. However, if the
protein is defective or absent, the virus can spread more easily, causing
severe disease.

The
antiviral role of IFITM3 in humans was first suggested by studies using a
genetic screen, which showed that the protein blocked the growth of influenza
virus and dengue virus in cells. This led the team to ask whether IFITM3
protected mice from viral infections. They removed the IFITM3 gene in mice and
found that once they contracted influenza, the symptoms became much more severe
compared to mice with IFITM3. In effect, they found the loss of this single
gene in mice can turn a mild case of influenza into a fatal infection.

The
researchers then sequenced the IFITM3 genes of 53 patients hospitalised with
influenza and found that some have a genetic mutant form of IFITM3, which is
rare in normal people. This variant makes cells more susceptible to viral
infection.

“Collectively,
the data reveals that the action of a single antiviral protein, IFITM3, can
profoundly alter the course of the flu and potentially other viruses in both
human and mouse,” explains senior co-author Professor Paul Kellam, who holds a
joint appointment at UCL Research Department of Infection and the Wellcome
Trust Sanger Institute. “To fully understand how both the protein and gene
control our susceptibility to viral infections, we need to study the mechanisms
of the gene variant more closely.

“Our
research is important for people who have this variant as we predict their
immune defences could be weakened to some virus infections. Ultimately as we
learn more about the genetics of susceptibility to viruses, then people can
take informed precautions, such as vaccination to prevent infection.”

This work on influenza complements
existing research in the UCL/MRC Centre for Medical Molecular Virology,
focusing on how viruses such as HIV have jumped species to cause disease in
humans, and how the use of next generation gene sequencing uncovers the mechanisms
whereby viruses can escape from vaccines and antiviral drugs.

"Paul Kellam’s
joint appointment provides enormous potential for linking the expertise on gene
sequencing at the Wellcome Trust Sanger Institute with UCL’s clinical research
environment,” says Professor Deenan Pillay, Head of UCL Research Department of
Infection. “This Nature paper
represents a significant advance in our understanding of why infections can hit
some people harder than others.”

Professor Greg Towers,
Wellcome Trust Senior Fellow in the UCL Research Department of Infection says:
“This is another fantastic example of how pathogens like flu
are controlled when they infect us. What is really interesting here is how
different people do better or worse after infection due to their genetic make-up."

Sir
Mark Walport, director of the Wellcome Trust, said: "During the recent
swine flu pandemic, many people found it remarkable that the same virus could
provoke only mild symptoms in most people, while, more rarely, threatening the
lives of others. This discovery points to a piece of the explanation: genetic
variations affect the way in which different people respond to infection.

“This
important research adds to a growing scientific understanding that genetic
factors affect the course of disease in more than one way. Genetic variations
in a virus can increase its virulence, but genetic variations in that virus’s
host – us – matter greatly as well.”

CollaborationThis research was a
collaboration between institutes in the United States and the United Kingdom.
The samples for this study were obtained from the MOSAIC consortium in England
and Scotland, co-ordinated from the Centre for Respiratory Infection (CRI) at
Imperial College London, and the GenISIS consortium in Scotland at the
University of Edinburgh. These were pivotal for the human genetics component of
the work.

FundingThis work was supported by the Wellcome Trust. The MOSAIC work
was supported by Imperial’s National Institute for Health Research
Comprehensive Biomedical Research Centre (cBRC), the Wellcome Trust and Medical
Research Council UK. The GenISIS work was supported by the Chief Scientist
Office (Scotland) and the Roslin Institute of the University of Edinburgh.
A.L.B. is the recipient of a Charles H. Hood Foundation Child Health Research Award,
and is supported by grants from the Phillip T. and Susan M. Ragon Institute
Foundation, the Bill and Melinda Gates Foundation’s Global Health Program and
the National Institute of Allergy and Infectious Diseases. J.K.B. is supported
by a Wellcome Trust Clinical Lectureship through the Edinburgh Clinical
Academic Track (ECAT)